Recent Developments of P-gp Inhibitors
Pp. 184-239 (56)
Sören Krawczyk, Christiane Baumert and Andreas Hilgeroth
Multidrug resistance (MDR) plays the central role in failing cancer therapy
regimes of today. The MDR phenomenon concerns various drugs of structurally related
as well as unrelated compound classes including also novel anticancer drugs. Formerly
drug-sensitive cancer cells lose their sensitivity and become resistant under theapy.
Although MDR is a multifactorial process, the main obstacle is the expression of
multidrug efflux pumps that lowers the intracellular drug levels by an active drug
transport out of the cells. P-glycoprotein (P-gp) is the longest identified efflux pump.
The attempt to overcome the MDR phenomenon by the use of inhibitors of the efflux
pump activities turned out as most promising beside other so far non-effective tries. So
far there exists no X-ray crystal structure analysis of P-gp which is difficult to
crystallize because of its transmembrane protein character. Thus, the development of Pgp
inhibitors has been a challenge for medicinal chemists. The article reviews advances
in P-gp inhibitor development by focussing on structure-activity relationships in the
different compound classes to document improvements up today. One success has been
the reduction of cytotoxic properties partly resulting from the originally
pharmacological compound properties. However, undesired drug interactions and
resulting toxicities limited clinical in vivo activities so far.
Multidrug resistance, P-gp inhibitor, structure-activity relationships,
Martin Luther University Halle-Wittenberg, Institute of Pharmacy, Wolfgang-Langenbeck-Strasse 4, D-06120 Halle (Saale), Germany